Abstract
High-density lipoprotein (HDL) homeostasis is important in maintaining both cardiovascular and renal health. Scavenger receptor class B type 1 (SR-B1), the major HDL receptor in mammals, plays a crucial role in reverse cholesterol transport and HDL metabolism. Evidence from mouse study has well demonstrated that HDL disorders caused by Srb1 inactivation accelerate atherosclerosis and even induce lethal cardiovascular diseases. However, the renal consequences of Srb1 dysfunction are still unknown. Here we explored this issue in both Srb1 knockout (Srb1-/-) mice and atherosclerotic low-density lipoprotein receptor knockout (Ldlr-/-) mice with Srb1 deletion. Our data showed that no apparent renal damage was observed in 5-month-old Srb1-/- mice fed on standard rodent chow diet as well as Srb1-/- mice fed on a high-fat diet (HFD) for 12 weeks. However, 5-month-old Srb1/Ldlr-/- mice fed on rodent chow had increased urinary albumin excretion and developed spontaneous intraglomerular Oil-red O (ORO)-positive lipoprotein deposition that is similar to lesions observed in human lipoprotein glomerulopathy (LPG). HFD feeding accelerated LPG-like lesions in Srb1/Ldlr-/- mice, inducing severe proteinuria and significantly promoting intraglomerular ORO-positive lipoprotein deposition. Interestingly, probucol reversed HFD-induced HDL disorders and almost fully abrogated LPG-like lesions in Srb1/Ldlr-/- mice. In conclusion, the present study demonstrates that SR-B1 dysfunction leads to LPG-like lesions in atherosclerotic mice, which could be rescued by probucol. SR-B1 loss-of-function mutant carriers therefore might be susceptible to developing metabolic nephropathy in addition to cardiovascular diseases, and probucol might be a potential therapeutics.
Highlights
High-density lipoproteins (HDLs) are traditionally known as cardio-protective lipoproteins for their crucial roles in reveres cholesterol transport (RCT) and possessing multiply antiinflammatory, anti-oxidant and anti-thrombotic functions [1]
When mice reached 5 months old on this standard rodent chow diet feeding, no significant change of renal function, reflected by 24-h urinary albumin excretion (UAE) and urinary creatinine (Ucr) level (Figure 1B), as well as glomerular morphology or size visualized by Periodic Acid-Schiff (PAS) staining, was observed in Srb1-/- mice, comparing with those in matched wild-type controls (Figures 1C,D)
No intraglomerular lipid deposition visualized by Oil-red O (ORO) staining, no inflammatory macrophage infiltration visualized by Mac2 immunohistochemical staining and no glomerular fibrosis visualized by Masson staining were observed in 5-month-old Srb1-/- mice (Figure 1C)
Summary
High-density lipoproteins (HDLs) are traditionally known as cardio-protective lipoproteins for their crucial roles in reveres cholesterol transport (RCT) and possessing multiply antiinflammatory, anti-oxidant and anti-thrombotic functions [1]. In addition to their well-known cardiovascular benefits, there are increasing evidence suggesting that these lipoproteins are closely associated with renal health and disease. Defective RCT and loss of HDL anti-inflammatory and anti-oxidant capacity due to HDL disorders might lead to renal injuries Both clinical and experimental evidence has showed that defective HDLs caused by ATP-binding cassette transporter type A1 and lecithin–cholesteryl acyltransferase (LCAT) deficiencies are underlying contributory factors for renal diseases [5]. Disruption of HDL metabolism is consequence of renal injuries and responsible for the development and progression of renal diseases, which might in turn facilitate cardiovascular consequences
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